Abstract Cigarette smoke is a major source of reactive oxidants, including free radicals and aldehydes, which are playing critical roles in the development and progression of most tobacco-caused diseases including lung cancer. With the rapidly growing popularity of electronic cigarettes (EC), there is growing concern about potential harm associated with their use. Using state-of-the-art high resolution analytical methods to detect and measure oxidants, we have demonstrated that EC aerosols contain significant levels of highly reactive free radicals and aldehydes. While these oxidants were detected in all types of EC tested, their levels varied substantially by EC product design, flavor additives, and usage behaviors. Based on these studies and the known importance of oxidative stress/damage and inflammation in lung carcinogenesis, our proposal focuses on the potential impact of EC-derived free radicals and aldehydes in mechanisms involved in lung cancer development. Specifically, we hypothesize that exposure to oxidants from EC use will lead to oxidative stress/damage and inflammation in the lung resulting in increased susceptibility to cancer. We will utilize a translational approach to test this hypothesis by first, in the laboratory, identifying the chemical identity and potential for harm for the major free radicals produced by EC (Aim 1), secondly conducting controlled exposure studies in a relevant mouse model on the impact of EC-aerosols on specific lung cancer-related endpoints and lung tumor development (Aim 2), and thirdly, conduct secondary analyses of samples generated from an NIDA-funded EC clinical trial to examine the impact of long-term switching from conventional cigarettes to ECs on relevant oxidative stress/damage and inflammatory biomarkers (Aim 3). In Aim 1, we utilize advanced electron paramagnetic resonance (EPR) spectroscopy techniques and liquid chromatography-tandem mass spectrometry (LC-MS/MS) methodologies to identify major radical species in representative EC devices (including the NIDA developed standardized EC, SREC). Aim 2 will consist of multiple short-term exposure studies in the A/J mouse, both in nave animals and those pre-exposed to cigarette smoke, and will also test the specific impact of flavorants, radicals and aldehydes on systemic and tissue specific biomarkers of oxidative stress/damage, inflammation and lung-cancer related pathways. Additionally, we will determine and compare the impact of EC aerosol and cigarette smoke exposure on lung tumorigenesis in an NNK-induced A/J mouse model. In Aim 3, the impact of switching from conventional cigarettes to EC on biomarkers of oxidative stress/damage and inflammation in healthy adult smokers will be determined. Our research approach is innovative based upon its novel focus on EC-derived free radicals, use of innovative methods and biomarkers, and its integrative translational design. With the completion of these studies, we hope to provide much needed information regarding the potential lung-cancer related harm associated with free radical and oxidant exposure from tobacco products which can be used for the development of regulatory policies aimed at EC products/usage.